Protease activated receptor-2 (PAR-2) belongs to G-protein-coupled receptor (GPCR), and was found in association with thrombin receptor (PAR-1) found in 1991. As the results of searching PAR-2 activation mechanism, the PAR-2 has been known to have a specific activation mechanism in that when a protease, such as trypsin or cell-derived tryptase, cleaves a specific site of a peptide sequence present at a terminal of an extracellular domain of the PAR-2, a peptide sequence appearing at a terminal of the receptor (for example, SLIGRL for human) is combined with a specific site of the PAR-2, which is then activated (Exp. Rev. Mol. Med. 4(16): 1-17, 2002).
It has been recently reported that the PAR-2 plays an important role in skin inflammation reaction, skin barrier function, and pruritus occurrence, and thereby a strong association between the role of the PAR-2 and atopic dermatitis showing all those symptoms as major disease symptoms are represented.
PAR-2 has been known to be exhibited in various cells of human, and has been reported to be effective in inducing inflammatory reactions, activation reactions of nerve cells, and the like. Also, it has been reported that the PAR-2 promotes transport of melanosome while being involved in signal transmission mechanism between keratinocyte and melanocyte in the skin, and thus is closely associated with pigmentation of the skin (Drug Dev. Res. 59: 408-416, 2003).
In addition, it has been recently reported that activation of the PAR-2 is very closely associated with the skin barrier function. That is, it has been reported that, when the skin barrier function is damaged, the activity of protease rapidly increase in the stratum corneum, which leads to activation of the PAR-2 (J. Invest Dermatol 126: 2074-2076, 2006), and it has been confirmed that a house dust mite- or roach-derived material, which is a kind of allergen, causing and exacerbating atopic dermatitis, also has an effect of activating the PAR-2. Previous studies of the present researcher showed that, when allergen is applied to the skin having disrupted skin barriers, the activation of PAR-2 inhibits the recovery of the skin barrier function, and when a PAR-2 inhibitor and allergen are simultaneously applied, the barrier recovery mechanism is normalized (J. Invest. Dermatol. 128: 1930-1939, 2008). Also, it was reported that the recovery of the skin barrier is promoted when the PAR-2 inhibitor is applied to the skin having disrupted skin barriers. In consideration that the skin barrier disruption is the most common symptom in the skin of patients with atopic dermatitis, this effect of the PAR-2 inhibitor of recovering disruption of the skin barrier is expected to be capable of helping improve the symptoms of atopic dermatitis.
It has been reported that intradermal activation of the PAR-2 causes pruritus, and it has been known that this pruritus causes scratching behavior. According to the existing research results on anti-pruritic effects of PAR-2 inhibitors (Japanese Patent Laid-Open Publication No. JP2004-170323), it has been reported that scratching behavior was significantly reduced when the PAR-2 inhibitor was applied to the skin. According to the known pruritic mechanism, nerve cells are activated by activation of PAR-2 present in the nerve fiber in the skin, and thus a signal of pruritic is transmitted to the brain. It was confirmed that, in an animal model where a PAR-2 activating material is applied to the skin, the function of PAR-2 associated with pruritic rapidly increased the number of times of scratching, and this phenomenon was suppressed when activation of the PAR-2 was inhibited (J. Neurosci. 2003, 23, 6176-6180).
As materials having a selective inhibitory efficiency to PAR-2, two species have been currently known all over the world, and one of them is ENMD-1,068 of EntreMed Company, a bio-venture company in the United States, of which efficacy was verified in an academic journal. Also, Japan Patent Laid-Open Publication No. 2004-170323 by Sumitomo Pharmacy Company discloses a PAR-2 inhibitor.

With respect to exacerbation of skin inflammation due to PAR-2 and anti-inflammatory effects of materials having PAR-2 inhibitory activity, it was confirmed that, when trypsin, which is a protease of activating PAR-2, or activating peptide (AP), which is a material of activating PAR-2, was applied to the skin, skin inflammation was increased, and when a protease inhibitor was together applied, the skin inflammation was reduced (FASEB J. 2003, 17, 1871-1885).
The present inventors synthesized various compounds for a long time in order to synthesize materials having PAR-2 inhibitory activity and confirmed activities thereof, and finally invented new compounds having excellent PAR-2 inhibitory activity.